Pulmonary arterial hypertension (PAH) is a progressive lung disorder which, untreated, leads to death on average within 2.8 years after being diagnosed. An increasing constriction of the pulmonary circulation leads to increased stress on the right heart, which may develop into right heart failure. PAH is a disease of uncertain etiology that leads to right ventricular failure, and ultimately death.
Although many causes and conditions are found to be associated with PAH, many of them share in common several fundamental pathophysiological features. One important feature among these processes is dysfunction of the endothelium, the internal cellular layer of all vessel walls, which is normally responsible for the production and metabolism of a large array of substances that regulate vessel tone and repair and inhibit clot formation. In the setting of PAH, endothelial dysfunction can lead to excessive production of deleterious substances and impaired production of protective substances. Whether this is the primary event in the development of PAH or part of a downstream cascade remains unknown, but in either case it is an important factor in the progressive vasoconstriction and vascular proliferation that characterize the disease.
Abnormalities in three major endothelium-based pathways have been identified that serve as the basis for current treatments for PAH:
(1) Overproduction of endothelin. Endothelin is a vasoconstrictor and angiogenic substance that is produced in excess by the injured endothelium in PAH. By blocking the receptor, endothelin-receptor antagonists (ERAs) neutralize the consequences of excessive endothelin synthesis and produce clinical benefit.
(2) Underproduction of Nitric Oxide (NO). Nitric oxide is a potent vasodilator and inhibitor of vascular proliferation that is under produced by the injured pulmonary vascular endothelium in PAH. Nitric oxide mediates these effects through cyclic GMP. By inhibiting the breakdown of the enzyme that catabolizes cGMP, phosphodiesterase type-5 inhibitors (PDE5) such as sildenafil and tadalafil augment cGMP, thereby minimizing the impact of diminished NO activity in PAH, with resulting clinical benefit.
(3) Underproduction of prostacyclin. Prostaglandins are a heterogeneous family of endoperoxides that are produced in a variety of organ systems and cells and have a number of important regulatory activities. In the vasculature, prostaglandin 12 (PGI2, prostacyclin) is the most abundant and important prostacyclin produced by the endothelium, and serves as a potent vasodilator and inhibitor of growth and proliferation. As with NO, prostacyclin production by the pulmonary vascular endothelium is diminished in the setting of PAH. Treatment of PAH with prostacyclin or an agonist thereof has resulted in clinical benefit in PAH.
Of the various therapeutic approaches to treat PAH currently available, prostacyclin-based therapies are probably the most potent. It has been shown that PGI2 agonists stimulate ATP release from erythrocytes via a signaling pathway that requires increases in cyclic adenosine monophosphate (cAMP). The erythrocyte-derived ATP is capable of vasodilating isolated-perfused lungs, the cells of which contain PGI2 receptors.
However, prostacyclin-based therapies often result in undesired side effects and delivery issues. Prostacyclin can be inactivated by a low pH, making it unsuitable for oral administration because the low pH in the stomach can inactivate the compound. Furthermore, the half-life of prostacyclin in the blood is 3-5 minutes, which can demand continuous delivery in order to achieve a sustained pharmacologic effect. Prostacyclin agonists address some issues related to undesired side effects and delivery issues, but a need remains to develop new methods for treating PAH, and new methods for screening for effective PGI2 agonists for treating PAH.